Inflammation is a localized protective response mounted by tissues in response to injury, infection, or tissue destruction resulting in the destruction of the infectious or injurious agent and isolation of the injured tissue. A typical inflammatory response proceeds as follows: recognition of an antigen as foreign or recognition of tissue damage, synthesis and release of soluble inflammatory mediators, recruitment of inflammatory cells to the site of infection or tissue damage, destruction and removal of the invading organism or damaged tissue, and deactivation of the system once the invading organism or damage has been resolved. In many human diseases with an inflammatory component, the normal, homeostatic mechanisms which attenuate the inflammatory responses are defective, resulting in damage and destruction of normal tissue. Consequently, much effort has been made to identify the molecular mechanisms underlying regulation of inflammatory responses.
For example, both TNF-alpha and IL-1 have been identified as important extracellular mediators that induce expression of a number of gene products involved in tissue inflammation (DiDonato et al., Nature, 1997, 388, 548-554). Although IL-1 and TNF-alpha bind to distinct cell surface receptors, it is currently believed that their intracellular signals ultimately converge to induce a similar spectrum of gene products through activation of the nuclear transcription factor NF-kappa-B (DiDonato et al., Nature, 1997, 388, 548-554). For several years, it has been known that NF-kappa-B normally exists in the cytoplasm bound to a family of inhibitor proteins known as IKB-alpha (Inhibitor-Kappa-B-alpha) and IKB-beta. Phosphorylation of the IKB's triggers them to be ubiquitinated and then degraded, thereby releasing NF-kappa-B, which is then free to translocate to the nucleus and activate expression of its downstream targets. Recently, two closely related kinases responsible for IKB phosphorylation (and hence NF-kappa-B activation) have been identified and are termed Inhibitor-kappa B Kinase-alpha (IKK-1, for I-Kappa-B Kinase 1) and Inhibitor-kappa b Kinase-beta (IKK-2, for I-Kappa-B Kinase 2) (DiDonato et al., Nature, 1997, 388, 548-554; Zandi et al., Science, 1998, 281, 1360-1363; Zandi et al., Cell, 1997, 91, 243-252).
It is currently believed that Inhibitor-kappa B Kinase-alpha and/or Inhibitor-kappa B Kinase-beta may represent the point at which the signal transduction pathways activated by TNF-alpha and IL-1 converge to generate active NF-kappa-B (DiDonato et al., Nature, 1997, 388, 548-554). It has therefore been proposed that inhibition of Inhibitor-kappa B Kinase-alpha or Inhibitor-kappa B Kinase-beta may represent a method to uniformly inhibit the diverse range of molecular signals that lead to activation of the inflammatory response (Israel, Nature, 1997, 388, 519-521). Recently, activation of Inhibitor-kappa B Kinase-alpha and Inhibitor-kappa B Kinase-beta by the HTLV-1 protein Tax was demonstrated (Geleziunas et al., Mol. Cell. Biol., 1998, 18, 5157-5165). Since activation of NF-kappa-B in HTLV infected T-cells has been implicated in the development of T-cell leukemia, it has been proposed that activation of Inhibitor-kappa B Kinase-alpha and/or Inhibitor-kappa B Kinase-beta through Tax may play a role in T-cell leukemia tumorigenesis as well (Geleziunas et al., Mol. Cell. Biol., 1998, 18, 5157-5165).
As a result of the role that Inhibitor-kappa B Kinase-beta activation is believed to play in the development of T-cell leukemia and in the activation of the inflammatory responses, there is a great desire to provide compositions of matter which can modulate the expression of Inhibitor-kappa B Kinase-beta.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Inhibitor-kappa B Kinase-beta. Consequently, there is a long-felt need for agents capable of effectively inhibiting Inhibitor-kappa B Kinase-beta. It is anticipated that oligonucleotides capable of modulating the expression of Inhibitor-kappa B Kinase-beta may provide for a novel class of therapeutic agents with activity towards a variety of inflammatory diseases or disorders or diseases with an inflammatory component such as asthma, juvenile diabetes mellitus, myasthenia gravis, Graves' disease, rheumatoid arthritis, allograft rejection, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus erythematosus, systemic lupus erythematosus, diabetes, multiple sclerosis, contact dermatitis, rhinitis and various allergies, or hyperproliferative disorders such as leukemias and other tumors. Antisense oligonucleotides against Inhibitor-kappa B Kinase-beta may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications.